Normal Control Individuals Research Articles

Impaired inhibition and working memory in response to internet-related words among adolescents with internet addiction: A comparison with attention-deficit/hyperactivity disorder

Impairments in response inhibition and working memory functions have been found to be closely associated with internet addiction (IA) symptoms and attention-deficit/hyperactivity disorder (ADHD) symptoms. In this study, we examined response inhibition and working memory processes with two different materials (internet-related and internet-unrelated stimuli) among adolescents with IA, ADHD and co-morbid IA/ADHD. Twenty-four individuals with IA, 28 individuals with ADHD, 17 individuals with IA/ADHD, and 26 matched normal controls (NC) individuals were recruited. All participants were measured with a Stop-Signal Task and 2-Back Task under the same experimental conditions. In comparison to the NC group, subjects with IA, ADHD and IA/ADHD demonstrated impaired inhibition and working memory. In addition, in comparison to internet-unrelated conditions, IA and co-morbid subjects performed worse on the internet-related condition in the Stop trials during the stop-signal task, and they showed better working memory on the internet-related condition in the 2-Back Task. The findings of our study suggest individuals with IA and IA/ADHD may be impaired in inhibition and working memory functions that might be linked to poor inhibition specifically related to internet-related stimuli, which will advance our understanding of IA and contribute to prevention and intervention strategies.

Application of molecular imaging combined with genetic screening in diagnosing MELAS, diabetes and recurrent pancreatitis.

We report molecular imaging combined with gene diagnosis in a family with 7 members who carried an A3243G mutation in mitochondrial tRNA and p.Thr 137 Met in cationic trypsinogen (PRSS1) gene presented with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), diabetes, and recurrent pancreatitis. DNA sequencing was used to detect and validate mitochondrial DNA and PRSS1. We also verified that mitochondrial heterozygous mutations and c.410 C>T mutation causing p.Thr 137 Met could be detected in oral epithelial cells or in urine sediment cells. In addition, molecular imaging was carried out in the affected family members. In this pedigree, MELAS syndrome accompanied by pancreatitis was an important clinical feature, followed by diabetes. Heteroplasmy of the mtDNA A3243G and c.410 C>T mutation of PRSS1 was found in all tissue samples of these patients, but no mutations were found in 520 normal control and normal individuals of the family. However, based on molecular imaging observations, patients with relatively higher lactate/pyruvate levels had more typical and more severe symptoms, particularly those of pancreatic disease (diabetes or pancreatitis). MELAS syndrome may be associated with pancreatitis. For the diagnosis, it is more reasonable to perform molecular imaging combined with gene diagnosis.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. National Institutes of Health and Howard Hughes Medical Institute.

Association of 14-bp insertion/deletion polymorphism of HLA-G gene with idiopathic recurrent miscarriages in infertility center patients in Yazd, Iran

HLA-G is supposed to play a pivotal role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. A 14-bp insertion and/or deletion polymorphism in exon-8 has a possible role in HLA-G expression. The present study analyzed the 14-bp insertion/deletion polymorphism in normal pregnancy and recurrent miscarriage patients in order to discover a possible correlation between the 14-bp polymorphism and recurrent miscarriage (RM). In this study, genomic DNA from 200 RM patients and 200 normal fertile control individuals using the routine salting out method were isolated. Exon-8 of HLA-G gene of the two groups were amplified using polymerase chain reaction and analyzed by electrophoresis on 10% non-denaturing polyacrylamide gel electrophoresis containing ethidium bromide and visualized under ultraviolet light. HLA-G allele frequencies and genotypes in RM women and the fertile control group were compared using a Chi-square test. The results showed that there was a difference in allelic frequencies of 14-bp insertion polymorphism between fertile controls and RM patients; the frequency of +14 bp/−14 bp heterozygotes was significantly higher in RM patients as compared with fertile controls. Furthermore, the frequency of +14-bp insertion allele was significantly higher in those with RM as compared with normal fertile controls. From the findings here, it was concluded that a 14-bp insertion/deletion polymorphism in exon 8 could play a possible role in recurrent miscarriages. These results might ultimately be of significance for clinicians and those involved in understanding infertility and RM.

Single nucleotide polymorphisms in premature ovarian failure-associated genes in a Chinese Hui population

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles in individuals <40 years old, and is a major cause of infertility in females. Genetic factors are considered to be responsible for the development of POF, however, the exact pathogenesis remains to be elucidated in the majority of cases. In the present study, the single nucleotide polymorphisms (SNPs) of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), inhibin βB (INHBB) and follicle stimulating hormone receptor (FSHR) genes were investigated, and their association with POF in a Chinese Hui population of the Ningxia Hui Autonomous Region in western China was evaluated. Peripheral blood samples were collected from 63 patients diagnosed with POF (POF group) and 58 normal control individuals (control group), from which the genomic DNA was isolated. The GDF9, BMP15, INHBB and FSHR genes were amplified using polymerase chain reaction assays, and their SNPs were determined by sequencing. In the four SNPs identified across the GDF9 loci, D57Y (169G>T), rs1049127 (546G>A), rs254286 (447C>T) and rs254285 (969C>G), the frequencies of the 546G>A genotype and allele A were significantly higher in the POF group, compared with the normal control group (34.92, vs. 6.90%; P<0.05 and 19.05, vs. 3.23%; P<0.05, repsectively), while no significant differences were observed in the occur rence of the c.447C>T and c.969C>G mutations between the two groups (60.32, vs. 50% and 50.79, vs. 55.17%, repsectively). The c.169G>T mutation within the GDF9 gene was only detected in two patients with POF, and the mutation did not occur in the normal control group. A total of three SNPs were detected within the BMP15 gene, including rs3810682 (−9C>G), rs79377927 (788_789insTCT) and rs17003221 (852C>T), and no significant differences were observed in the frequencies of the 9C>G and 852C>T genotypes between the POF and control groups (7.94, vs. 6.90% and 4.76, vs. 3.45%, respectively). The 788_789insTCT genotype was detected in only two patients with POF. A novel mutation, c.1095C>A, was identified in exon 2 of the INHBB gene, however, no significant difference was found in the occurrence of the mutation between the two groups (30.16, vs. 22.41%; P>0.05). The rs6165 (919G>A) and rs6166 (2039G>A) SNPs were detected in exon 10 of the FSHR gene; however, no significant difference was observed in the genotype frequencies between the two groups (92.06, vs. 91.38% and 96.83, vs. 93.10%, respecrively). These results demonstrated that GDF9 c.169G>T (D57Y), c.546G>A (rs1049127), and BMP15 rs79377927 (788_789insTCT) were associated with POF in the Chinese Hui population.

Expression of Endoplasmic Reticulum Stress Related Genes in Blood Cells of Obese Boys with and without Insulin Resistance

Objective: to study the changes in the expression level of the subset of genes, encoding for important cell growth factors and enzymes, which play an important role in the control of cellular growth and apoptosis, in blood cells of obese boys with and without insulin resistance for evaluation of its possible significance in the development of obesity and impaired insulin sensitivity. Material and Methods: We studied the expression of genes, which are responsible for control of cell growth and survival, in blood cells of obese boys with normal and impaired insulin sensitivity as compared to normal (control) individuals. Results: It was shown that the expression level of PLAGL, CYR61, ITGA5, and TFPI2 genes is increased, but the GADD45A gene is decreased in blood cells of obese children with normal insulin sensitivity as compared to the control group. Insulin resistance in obese boys leads to the up-regulation of PPP1R15A and PLAGL1 gene expressions as well as to the down-regulation of TFPI2, GADD45A, ALDH1A2, CYR61, and HSPA6 genes in blood cells as compared to obese patients with normal insulin sensitivity. Conclusion: Results of this study provide evidence that obesity affects the expression of the subset of genes related to the control of cell growth and survival in blood cells and that impaired insulin sensitivity in obesity is associated with changes in the expression level of PLAGL, CYR61, GADD45A, PPP1R15A, TFPI2, ALDH1A2, and HSPA6 genes, which possibly contributes to the development of obesity and its metabolic complications, including insulin resistance.

IgE Anti-LJM11 Sand Fly Salivary Antigen May Herald the Onset of Fogo Selvagem in Endemic Brazilian Regions

IgE Anti-LJM11 Sand Fly Salivary Antigen May Herald the Onset of Fogo Selvagem in Endemic Brazilian Regions

Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease.

There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue. To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships. We measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium. A comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity. The PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = -0.48; P < .01) and tangles (Pearson r = -0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex. Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.

The expression of CCN2, IQSEC, RSPO1, DNAJC15, RIPK2, IL13RA2, IRS1, and IRS2 genes in blood of obese boys with insulin resistance.

The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes via changes in the expression of numerous regulatory genes. We studied the expression of the subset of genes, which responsible for control of cell growth and glucose metabolism, in blood cells of obese boys with normal and impaired insulin sensitivity as well as in normal (control) individuals. It was shown that obesity with normal insulin sensitivity enhances the expression of IRS1, RIPK2, IL13RA2, RSPO1, IQSEC, and CCN2 genes but decreases the expression level IRS2 and DNAJC15 genes in the blood cells as compared to control group. Insulin resistance in obese boys leads to up-regulation of IRS2, RSPO1, and DNAJC15 gene expressions as wells to down-regulation of IRS1 and RIPK2 genes in the blood cells versus obese patients with normal insulin sensitivity. Results of this study provide evidence that obesity affects the expression of the subset of genes related to cell growth and glucose metabolism in blood cells and that insulin resistance in obesity is associated with changes in the expression level of IRS1, IRS2, RIPK2, RSPO1, and DNA JC15 genes, which contribute to the development of insulin resistance and glucose intolerance and possibly reflect some changes in fat tissue.

Characterization of lipid parameters in diabetic and non-diabetic atherosclerotic patients.

Background & ObjectiveThe relationship between lipid profile perturbation and diabetes associated complications has long been an area of interest. Dyslipidemia is a potent predictor of cardiovascular morbidity and mortality in diabetic patients. The aim of present study was to investigate relationship between aging and lipid profiles in diabetic and non-diabetic atherosclerotic patients.MethodsFive hundred and seventy six individuals (45–75 year age) participated in this study. Among these, 192 were having history of diabetes mellitus and atherosclerosis. Individuals are categorized on the base of health (normal, non-diabetic atherosclerosis, diabetic atherosclerosis) and age (45–55 years, 56–65 years, and 66–75 years). All the participants were subjected to the procedures like a detailed history, biochemical analysis for fasting blood sugar, hemoglobin A1c, total cholesterol (TC), triglycerides (TG), low-density lipoprotein-(LDL), very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL). All these parameters were compared between diabetic and non-diabetic atherosclerotic patients of all three age groups. TC/HDL and LDL/HDL were also calculated.ResultsDiabetic atherosclerotic individuals (both males and females) had high level of TC, TG, LDL, VLDL and low level of HDL in comparison to non-diabetic atherosclerotic and normal control individuals. Among all three age groups, lipoprotein abnormality was observed to be more frequent in females than males. There was a significant increase in TC/HDL and LDL/HDL ratio in diabetic atherosclerotic subjects compared to age and sex matched non-diabetic atherosclerotic and normal control.ConclusionsDegree of dyslipidemia increases with increase in age in both genders. Female are more prone to diabetic dyslipidemia and hence have more risk of developing atherosclerosis with increasing age.

The SALL4 gene in acute leukemias

Background The SALL gene family is involved in normal development as well as tumor genesis. SALL4 is essential for the maintenance of the pluripotent and the self-renewal properties of embryonic stem cells. Patients and methods It was conducted from the period of April 2008 to June 2012 on 40 patients with acute leukemia (group I), 20 patients who had nonmalignant hematologic disease (group II), and 20 healthy individuals (group III). They were subjected to laboratory investigations including a complete blood picture, RT-PCR for the detection of the SALL4 gene, for group I bone marrow aspiration biopsy, cytochemical studies, and immunophenotyping of either peripheral blood or bone marrow samples to diagnose and classify the hematologic malignancy. Results SALL4 mRNA was expressed in 50% of the acute myeloid leukemia (AML) cases and was undetectable in 50% of the cases. Whereas it was expressed in only 20% of acute lymphoblastic leukemia (ALL), it was undetectable in 80% of ALL. SALL4 mRNA was undetectable in all cases of immune thrombocytopenic purpura (group II) (0%). SALL4 mRNA was undetectable in all samples of the control group (group III) (0%). There was no significant difference between the expression level of CD markers and SALL4 in AML cases, whereas there was a significant elevation of the CD10 expression level in SALL4-positive ALL cases (P < 0.05). There was a significant reduction in the RBC count and the hematocrite (Hct) and platelet level in SALL4-positive ALL cases (P < 0.05), and there was a statistically significant reduction in the platelet count in SALL4-positive AML cases.Conclusion SALL4 mRNA expression was higher in cases of AML (50%), compared with ALL cases (20%). There was no SALL4 mRNA expression detected in all cases of immune thrombocytopenic purpura patients and in normal control individuals.

Analysis of Vertical Ground Reaction Force Variables Using Foot Scans in Hemiplegic Patients.

ObjectiveTo analyze the differences in the vertical ground reaction force (GRF) variables of hemiplegic patients compared with a control group, and between the affected and unaffected limbs of hemiplegic patients using foot scans.MethodsPatients (n=20) with hemiplegia and healthy volunteers (n=20) underwent vertical force analysis. We measured the following: the first and second peak forces (F1, F2) and the percent stances at which they occurred (T1, T2); the vertical force impulse (VFI) and stance times. The GRF results were compared between the hemiplegic patients and control individuals, and between the affected and unaffected limbs of hemiplegic patients. Additionally, we analyzed the impulse of the unaffected limb according to the motor assessment scale (MAS), Brunnstrom stage, and a Timed Up and Go Test.ResultsThe F1s and F2s of the affected and unaffected limbs were significantly less than those of the normal control individuals (p<0.05). The T1s of both the affected and unaffected limbs of the patients were greater than control individuals, whilst the T2s were lower (p<0.05). Greater impulses and stance times were recorded on both sides of the patients than in the limbs of the control individuals (p<0.05). The MAS, Brunnstrom stage and Timed Up and Go Test results were significantly correlated with the VFI of the unaffected limbs (p<0.05).ConclusionThe high impulse values of the unaffected limb were associated with complications during gait rehabilitation. Therefore, these results suggest that unaffected limbs should also be taken into consideration in these patients.

NPY1R is a novel peripheral blood marker predictive of metastasis and prognosis in breast cancer patients.

The aim of the current study was to evaluate a novel tumor marker, neuropeptide Y receptor Y1 (NPY1R), for the detection of circulating cancer cells and to investigate its clinical significance in breast cancer patients. The Digital Gene Expression Displayer tool of the Cancer Genome Anatomy Project was used to identify the marker gene NPY1R, which is able to detect circulating cancer cells. Nested quantitative polymerase chain reaction was performed to correlate the NPY1R expression levels with the clinicopathological features of 142 breast cancer patients. A follow-up study of 131 of the breast cancer patients was conducted for 38 months. Compared with the 60 normal control individuals, NPY1R was highly expressed in the cancer patients (P<0.01). These high levels of NPY1R expression were positively correlated with the clinical stage and lymph node metastasis status of the disease, as well as with the status of the estrogen and progesterone receptors (P<0.05). Breast cancer patients with circulating cancer cells that expressed NPY1R exhibited shorter tumor-specific survival when compared with those with no NPY1R expression (P<0.01). Additionally, the mortality rate was associated with HER2 expression in the NPY1R positive and negative groups. These results indicate that NPY1R may serve as a useful marker to predict breast cancer metastasis and to evaluate the prognosis of breast cancer patients.

Abstract 889: MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis

Abstract Early prevention of renal cell carcinoma needs a reliable and robust bioassay to evaluate kidney cancer patients. As a novel class of regulatory molecules in cellular activity, the recent studies showed that microRNAs had tissue-specific patterns and were able to distinguish the cancer from benign disease. We explored the diagnostic value of urine microRNAs from a cohort of 160 individuals: 80 patients with renal clear cell carcinoma and 80 normal control individuals. Material and methods: The renal clear cell carcinomas cohort included 63% stage I cases, 10% stage II cases, 19% stage III cases, 7% stage IV cases, 1% unknown cases. Normal control cohort included 34% diverticulosis cases, 15% bariatric surgery cases, 14% diverticulitis cases, 15% hernia surgery cases, 10% hemorrhoids cases and 12% other non-cancer conditions. Every 10 urine samples were pooled together and subjected to microRNA extraction. The Norgen Biotek urine microRNA purification kit was used for total microRNA extraction (including free floating microRNAs and microRNAs from exfoliated cells) in the pooled urine samples. Urine microRNA expression profiling was performed using nCounter miRNA Expression Assay. After ligation and purification, hybridized microRNAs sequences were label by specific color codes and quantified using nCounter Digital Analyzer, then the data were normalized to the sum of the microRNAs within each pooled sample before statistic analysis. Result: comparing to normal control urine samples, microRNA-21-5p expression showed upregulation in kidney urine samples, which is consistent with TCGA kidney cancer tissue profiling results. Some recent studies also demonstrated that microRNA-21 may act as an oncomir in prostate, lung and colorectal cancers. We also observed that microRNA-1268a and microRNA-549 were highly expressed in urine samples from renal cell carcinoma patients. Conclusion: These findings indicate that in urine microRNA-21-5p may serve as a potential molecular marker for renal cell carcinoma and provide a new approach in the diagnosis of kidney cancer. Note: This abstract was not presented at the meeting. Citation Format: Wei Meng, Hansjuerg Alder, Kirsteen Maclean, Simon Kirste, Petra Stegmaier, Anca Grosu, Arnab Chakravarti, Tim Lautenschlaeger. MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 889. doi:10.1158/1538-7445.AM2014-889

Assessment of left atrium mechanical function by deformation imaging in atrial fibrillation and its correlation with CHA2DS2-VASc risk score

Abstract Objectives Evaluation of left atrium (LA) mechanical function by speckle tracking based strain (SPTS) in patients with chronic non-valvular atrial fibrillation (AF) and its correlation with CHA 2 DS 2 -VASc risk score. Background AF is a progressive condition that begins with increased hemodynamic load or structural remodeling of the atria, understanding atrial function could lead to better ability to predict the risk of developing stroke and the response to treatment. SPTS is a recently emerged modality that accurately estimates myocardial function. Methods Sixty patients with chronic AF and 20 age and sex matched normal control individuals underwent conventional echo where LV dimensions, wall thickness, EF, LA diameter and volumes were measured. Peak left atrial longitudinal strain (PALS) was measured in apical four (AP4) and two chamber view (AP2) and its correlation with CHA 2 DS 2 -VASc risk score in the AF group was evaluated. Results LA diameter and volumes were greater in AF patients ( P -value 2 DS 2 -VASc score. Also, there was no significant difference between PALS in patients with CHA 2 DS 2 -VASc score less than and more than two points. Conclusion AF leads to impairment of LA mechanical function as evidenced by low PALS but PALS was not significantly correlated with CHA 2 DS 2 -VASc score. Also, there was no significantly statistical difference between PALS in patients with low and high CHA 2 DS 2 -VASc scores.

Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development.

Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression. NRG1 type I-IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0-83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined. Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing. To the authors' knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins.

Grey-matter volume as a potential feature for the classification of Alzheimer's disease and mild cognitive impairment: an exploratory study.

Specific patterns of brain atrophy may be helpful in the diagnosis of Alzheimer's disease (AD). In the present study, we set out to evaluate the utility of grey-matter volume in the classification of AD and amnestic mild cognitive impairment (aMCI) compared to normal control (NC) individuals. Voxel-based morphometric analyses were performed on structural MRIs from 35 AD patients, 27 aMCI patients, and 27 NC participants. A two-sample two-tailed t-test was computed between the NC and AD groups to create a map of abnormal grey matter in AD. The brain areas with significant differences were extracted as regions of interest (ROIs), and the grey-matter volumes in the ROIs of the aMCI patients were included to evaluate the patterns of change across different disease severities. Next, correlation analyses between the grey-matter volumes in the ROIs and all clinical variables were performed in aMCI and AD patients to determine whether they varied with disease progression. The results revealed significantly decreased grey matter in the bilateral hippocampus/parahippocampus, the bilateral superior/middle temporal gyri, and the right precuneus in AD patients. The grey-matter volumes were positively correlated with clinical variables. Finally, we performed exploratory linear discriminative analyses to assess the classifying capacity of grey-matter volumes in the bilateral hippocampus and parahippocampus among AD, aMCI, and NC. Leave-one-out cross-validation analyses demonstrated that grey-matter volumes in hippocampus and parahippocampus accurately distinguished AD from NC. These findings indicate that grey-matter volumes are useful in the classification of AD.

EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness

BackgroundAlmost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness.MethodWhole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved.ResultsA biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8−/− mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia.ConclusionThis new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.

Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia.

UPDATE ON THERAPEUTICS: IMPROVING THE CLINICAL YIELD

The goal of the study was to examine mismatch negativity (MMN) in schizotypal personality disorder (SPD) individuals. Abnormal MMN has been a consistent finding in chronic schizophrenia and there also have been reports of reduced duration MMN in first episode schizophrenia patients [Umbricht, D., Krljes, S., Mismatch negativity in schizophrenia: a meta-analysis. Schizophrenia Research (2005); 76(1):1–23], with some studies finding no pitch MMN amplitude differences [Salisbury, D.F., Shenton, M.E., Griggs, C.B., Bonner-Jackson, A., McCarley, R.W., Mismatch negativity n chronic schizophrenia and first-episode schizophrenia. Archives of General Psychiatry (2002); 59(8):686–694.], while others reporting a modest reduction [Umbricht, D.S., Bates, J.A., Lieberman, J.A., Kane, J.M., Javitt, D.C., Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biological Psychiatry (2006); 59(8):762–772], in recent onset schizophrenia patients. To our knowledge no reports exist of MMN in SPD individuals.Twenty six normal (14 females) control and 23 SPD (12 females) individuals were tested using the pitch MMN paradigm. Normal control (NC) and SPD individuals were recruited from the general population and assessed using DSM-IV. SPD individuals were included if they met 5 or more criteria for SPD disorder. The subjects listened to 2000 frequent 1 kHz pure tones and 100 rare 1.2 kHz pure tones while reading a magazine article. MMN was measured from a difference waveform within the latency window of 175–276 ms.Reduced MMN amplitude was found in SPD relative to NC subjects (p < 0.045).These results point to potential differences between SPD and schizophrenia, where no reduction in MMN was found in most studies of first episode patients.